In the US, about 75 million people have hypertension. About 81% of these people are aware that they have hypertension, only 73% are being treated, and only 51% have adequately controlled BP. In adults, hypertension occurs more often in blacks (41%) than in whites (28%) or Mexican Americans (28%), and morbidity and mortality are greater in blacks.

Blood pressure increases with age. About two thirds of people > 65 have hypertension, and people with a normal BP at age 55 have a 90% lifetime risk of developing hypertension. Because hypertension becomes so common with age, the age-related increase in BP may seem innocuous, but higher BP increases morbidity and mortality risk. Hypertension may develop during pregnancy (see Hypertension in Pregnancy and see Preeclampsia and Eclampsia).

Etiology

Hypertension may be

Primary (85 to 95% of cases)

Secondary

Primary hypertension

Hemodynamics and physiologic components (eg, plasma volume, activity of the renin-angiotensin system) vary, indicating that primary hypertension is unlikely to have a single cause. Even if one factor is initially responsible, multiple factors are probably involved in sustaining elevated blood pressure (the mosaic theory). In afferent systemic arterioles, malfunction of ion pumps on sarcolemmal membranes of smooth muscle cells may lead to chronically increased vascular tone. Heredity is a predisposing factor, but the exact mechanism is unclear. Environmental factors (eg, dietary sodium, obesity, stress) seem to affect only genetically susceptible people at younger ages; however, in patients > 65, high sodium intake is more likely to precipitate hypertension.

Pathophysiology

In most patients, CO is normal or slightly increased, and TPR is increased. This pattern is typical of primary hypertension and hypertension due to primary aldosteronism, pheochromocytoma, renovascular disease, and renal parenchymal disease.

In other patients, CO is increased (possibly because of venoconstriction in large veins), and TPR is inappropriately normal for the level of CO. Later in the disorder, TPR increases and CO returns to normal, probably because of autoregulation. Some disorders that increase CO (thyrotoxicosis, arteriovenous fistula, aortic regurgitation), particularly when stroke volume is increased, cause isolated systolic hypertension. Some elderly patients have isolated systolic hypertension with normal or low CO, probably due to inelasticity of the aorta and its major branches. Patients with high, fixed diastolic pressures often have decreased CO.

Plasma volume tends to decrease as BP increases; rarely, plasma volume remains normal or increases. Plasma volume tends to be high in hypertension due to primary aldosteronism or renal parenchymal disease and may be quite low in hypertension due to pheochromocytoma. Renal blood flow gradually decreases as diastolic BP increases and arteriolar sclerosis begins. GFR remains normal until late in the disorder; as a result, the filtration fraction is increased. Coronary, cerebral, and muscle blood flow is maintained unless severe atherosclerosis coexists in these vascular beds.

Abnormal sodium transport

In many cases of hypertension, sodium transport across the cell wall is abnormal, because the sodium-potassium pump (Na+, K+-ATPase) is defective or inhibited or because permeability to sodium ions is increased. The result is increased intracellular sodium, which makes the cell more sensitive to sympathetic stimulation. Calcium follows sodium, so accumulation of intracellular calcium may be responsible for the increased sensitivity. Because Na+, K+-ATPase may pump norepinephrine back into sympathetic neurons (thus inactivating this neurotransmitter), inhibition of this mechanism could also enhance the effect of norepinephrine, increasing BP. Defects in sodium transport may occur in normotensive children of hypertensive parents.

Sympathetic nervous system

Sympathetic stimulation increases blood pressure, usually more in patients with prehypertension (systolic BP 120 to 139 mm Hg, diastolic BP 80 to 89 mm Hg) or hypertension (systolic BP ≥ 140 mm Hg, diastolic BP ≥ 90 mm Hg, or both) than in normotensive patients. Whether this hyperresponsiveness resides in the sympathetic nervous system or in the myocardium and vascular smooth muscle is unknown. A high resting pulse rate, which may result from increased sympathetic nervous activity, is a well-known predictor of hypertension. In some hypertensive patients, circulating plasma catecholamine levels during rest are higher than normal.

Renin-angiotensin-aldosterone system

This system helps regulate blood volume and therefore blood pressure. Renin, an enzyme formed in the juxtaglomerular apparatus, catalyzes conversion of angiotensinogen to angiotensin I. This inactive product is cleaved by ACE, mainly in the lungs but also in the kidneys and brain, to angiotensin II, a potent vasoconstrictor that also stimulates autonomic centers in the brain to increase sympathetic discharge and stimulates release of aldosterone and vasopressin. Aldosterone and vasopressin cause sodium and water retention, elevating BP. Aldosterone also enhances potassium excretion; low plasma potassium (< 3.5 mEq/L) increases vasoconstriction through closure of potassium channels. Angiotensin III, present in the circulation, stimulates aldosterone release as actively as angiotensin II but has much less pressor activity. Because chymase enzymes also convert angiotensin I to angiotensin II, drugs that inhibit ACE do not fully suppress angiotensin II production.

Renin secretion is controlled by at least 4 mechanisms, which are not mutually exclusive:

A renal vascular receptor responds to changes in tension in the afferent arteriolar wall

A macula densa receptor detects changes in the delivery rate or concentration of sodium chloride in the distal tubule

Circulating angiotensin has a negative feedback effect on renin secretion

Angiotensin is generally acknowledged to be responsible for renovascular hypertension, at least in the early phase, but the role of the renin-angiotensin-aldosterone system in primary hypertension is not established. However, in black and elderly patients with hypertension, renin levels tend to be low. The elderly also tend to have low angiotensin II levels.

Hypertension due to chronic renal parenchymal disease (renoprival hypertension) results from the combination of a renin-dependent mechanism and a volume-dependent mechanism. In most cases, increased renin activity is not evident in peripheral blood. Hypertension is typically moderate and sensitive to sodium and water balance.

Vasodilator deficiency

Deficiency of a vasodilator (eg, bradykinin, nitric oxide) rather than excess of a vasoconstrictor (eg, angiotensin, norepinephrine) may cause hypertension. If the kidneys do not produce adequate amounts of vasodilators (because of renal parenchymal disease or bilateral nephrectomy), blood pressure can increase. Vasodilators and vasoconstrictors (mainly endothelin) are also produced in endothelial cells. Therefore, endothelial dysfunction greatly affects BP.

The mechanism involves development of generalized arteriolosclerosis and acceleration of atherogenesis. Arteriolosclerosis is characterized by medial hypertrophy, hyperplasia, and hyalinization; it is particularly apparent in small arterioles, notably in the eyes and the kidneys. In the kidneys, the changes narrow the arteriolar lumen, increasing TPR; thus, hypertension leads to more hypertension. Furthermore, once arteries are narrowed, any slight additional shortening of already hypertrophied smooth muscle reduces the lumen to a greater extent than in normal-diameter arteries. These effects may explain why the longer hypertension has existed, the less likely specific treatment (eg, renovascular surgery) for secondary causes is to restore blood pressure to normal.

Because of increased afterload, the left ventricle gradually hypertrophies, causing diastolic dysfunction. The ventricle eventually dilates, causing dilated cardiomyopathy and heart failure (HF) due to systolic dysfunction often worsened by arteriosclerotic CAD. Thoracic aortic dissection is typically a consequence of hypertension; almost all patients with abdominal aortic aneurysms have hypertension.

Evaluate for pheochromocytoma or a sleep disorder if BP elevation sudden and labile or severe

Hypertension is diagnosed and classified by sphygmomanometry. History, physical examination, and other tests help identify etiology and determine whether target organs are damaged.

Blood pressure must be measured twice—first with the patient supine or seated, then after the patient has been standing for ≥ 2 min—on 3 separate days. The average of these measurements is used for diagnosis. BP is classified as normal, prehypertension, or stage 1 (mild) or stage 2 hypertension (see Table: JNC 7 Classification of Blood Pressure in Adults). Normal blood pressure is much lower for infants and children.

Ideally, BP is measured after the patient rests > 5 min and at different times of day. A BP cuff is applied to the upper arm. An appropriately sized cuff covers two thirds of the biceps; the bladder is long enough to encircle > 80% of the arm, and bladder width equals at least 40% of the arm’s circumference. Thus, obese patients require large cuffs. The health care practitioner inflates the cuff above the expected systolic pressure and gradually releases the air while listening over the brachial artery. The pressure at which the first heartbeat is heard as the pressure falls is systolic BP. Total disappearance of the sound marks diastolic BP. The same principles are followed to measure BP in a forearm (radial artery) and thigh (popliteal artery). Sphygmomanometers that contain mercury are most accurate. Mechanical devices should be calibrated periodically; automated readers are often inaccurate.

BP is measured in both arms. BP > 15 mm Hg higher in one arm than the other is associated with higher mortality, and requires evaluation of the upper vasculature when this pattern of measurement is found. BP is also measured in a thigh (with a much larger cuff) to rule out coarctation of the aorta, particularly in patients with diminished or delayed femoral pulses; with coarctation, BP is significantly lower in the legs. If BP is in the low-hypertensive range or is markedly labile, more BP measurements are desirable. BP measurements may be sporadically high before hypertension becomes sustained; this phenomenon probably accounts for “white coat hypertension,” in which BP is elevated when measured in the physician’s office but normal when measured at home or by ambulatory BP monitoring. However, extreme BP elevation alternating with normal readings is unusual and possibly suggests pheochromocytoma, a sleep disorder such as sleep apnea, or unacknowledged drug use.

History

The history includes the known duration of hypertension and previously recorded levels; any history or symptoms of CAD, HF, or other relevant coexisting disorders (eg, stroke, renal dysfunction, peripheral arterial disease, dyslipidemia, diabetes, gout); and a family history of any of these disorders. Social history includes exercise levels and use of tobacco, alcohol, and stimulant drugs (prescribed and illicit). A dietary history focuses on intake of salt and stimulants (eg, tea, coffee, caffeine-containing sodas, energy drinks).

Physical examination

The physical examination includes measurement of height, weight, and waist circumference; funduscopic examination for retinopathy; auscultation for bruits in the neck and abdomen; and a full cardiac, respiratory, and neurologic examination. The abdomen is palpated for kidney enlargement and abdominal masses. Peripheral arterial pulses are evaluated; diminished or delayed femoral pulses suggest aortic coarctation, particularly in patients < 30. A unilateral renal artery bruit may be heard in slim patients with renovascular hypertension.

Testing

The more severe the hypertension and the younger the patient, the more extensive is the evaluation. Generally, when hypertension is newly diagnosed, routine testing is done to

Depending on results of initial tests and examination, other tests may be needed. If urinalysis detects albuminuria (proteinuria), cylindruria, or microhematuria or if serum creatinine is elevated (≥ 1.4 mg/dL [124 μmol/L] in men; ≥ 1.2 mg/dL [106 μmol/L] in women), renal ultrasonography to evaluate kidney size may provide useful information. Patients with hypokalemia unrelated to diuretic use are evaluated for primary aldosteronism and high salt intake.

On ECG, a broad, notched P-wave indicates atrial hypertrophy and, although nonspecific, may be one of the earliest signs of hypertensive heart disease. Left ventricular hypertrophy, indicated by a sustained apical thrust and elevated QRS voltage with or without evidence of ischemia, may occur later. If either of these findings is present, echocardiography is often done. In patients with an abnormal lipid profile or symptoms of CAD, tests for other cardiovascular risk factors (eg, C-reactive protein) may be useful.

If coarctation of the aorta is suspected, chest x-ray, echocardiography, CT, or MRI helps confirm the diagnosis.

Patients with labile, significantly elevated BP and symptoms such as headache, palpitations, tachycardia, excessive perspiration, tremor, and pallor are screened for pheochromocytoma (eg, by measuring plasma free metanephrines). A sleep study should also be strongly considered.

JNC 7 Classification of Blood Pressure in Adults

JNC= Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Prognosis

The higher the blood pressure and the more severe the retinal changes and other evidence of target-organ involvement, the worse is the prognosis. Systolic BP predicts fatal and nonfatal cardiovascular events better than diastolic BP. Without treatment, 1-yr survival is < 10% in patients with retinal sclerosis, cotton-wool exudates, arteriolar narrowing, and hemorrhage (grade 3 retinopathy), and < 5% in patients with the same changes plus papilledema (grade 4 retinopathy). CAD is the most common cause of death among treated hypertensive patients. Ischemic or hemorrhagic stroke is a common consequence of inadequately treated hypertension. However, effective control of hypertension prevents most complications and prolongs life.

Treatment

Drugs if BP is initially high (>160/100 mm Hg) or unresponsive to lifestyle modifications

Primary hypertension has no cure, but some causes of secondary hypertension can be corrected. In all cases, control of blood pressure can significantly limit adverse consequences. Despite the theoretical efficacy of treatment, BP is lowered to the desired level in only one third of hypertensive patients in the US.

JNC 8 recommends treatment targets for the general population:

For all patients, including all those with a kidney disorder or diabetes, treatment aims to reduce BP to < 140/90 mm Hg

For patients ≥ 60, treatment aims to reduce BP to < 150/90 mm Hg

However, some clinicians believe that certain patients should have a lower treatment goal of systolic BP 125 to 130 mm Hg (if BP is measured by standard manual office readings) or 120 to 125 mm Hg (if BP is measured with an automatic digital monitor). This includes patients > 50 yr of age who are considered high-risk for cardiovascular events (age > 75 yr, history of CAD or chronic kidney disease, Framingham risk score > 15%). Some clinicians also believe the systolic BP goal of 125 to 130 mm Hg should apply to certain patients with diabetes, eg, those with diabetic nephropathy and proteinuria (500 mg/day).

The benefits of lowering BP to levels approaching 120 mm Hg systolic should be weighed with the higher risk of dizziness and light-headedness and possible worsening of kidney function.

Even the elderly and frail elderly can tolerate a diastolic BP as low as 60 to 65 mm Hg well and without an increase in cardiovascular events. Ideally, patients or family members measure BP at home, provided they have been trained to do so, they are closely monitored, and the sphygmomanometer is regularly calibrated. Treatment of hypertension during pregnancy requires special considerations because some antihypertensive drugs can harm the fetus.

In stage 1 (mild) hypertension with no signs of target-organ damage, lifestyle changes may make drugs unnecessary. Patients with uncomplicated hypertension do not need to restrict their activities as long as blood pressure is controlled. Dietary modifications can also help control diabetes, obesity, and dyslipidemias. Patients with prehypertension are encouraged to follow these lifestyle recommendations.

For most patients with hypertension, one drug is given initially. For non-black patients, including those with diabetes, initial treatment should be with either an ACE inhibitor, angiotensin receptor blocker, calcium channel blocker, or a thiazide-like diuretic (chlorthalidone or indapamide). For black patients, including those with diabetes, a calcium channel blocker or a thiazide-like diuretic is recommended initially. Some antihypertensives are contraindicated in certain disorders (eg, beta-blockers in asthma) or are indicated particularly for hypertensive patients with certain disorders (eg, calcium channel blockers for angina pectoris, ACE inhibitors or angiotensin II receptor blockers for diabetes with proteinuria—see Table: Initial Choice of Antihypertensive Drug Class , see Figure: Algorithm for treatment of hypertension in patients ≥ 18 yr., and Antihypertensives for High-Risk Patients).

If the target BP is not achieved in 1 mo, the dose of the initial drug can be increased or a second drug added (selected from the drugs recommended for initial treatment). Note that an ACE inhibitor and an angiotensin receptor blocker should not be used together. Therapy is titrated frequently. If target BP cannot be achieved with 2 drugs, a third drug from the initial group is added. If such a third drug is not available (eg, for black patients) or tolerated, a drug from another class (eg, beta-blocker, aldosterone antagonist) can be used. Patients with such difficult to control BP may benefit from consultation with a hypertension specialist.

Data from James PA, Oparil S, Carter BL, et al: 2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National committee (JNC 8). JAMA 311 (5): 507-520, 2014.

If initial systolic BP is > 160 mm Hg, 2 drugs are often used from the start. An appropriate combination and dose are determined; many are available as single tablets, which improve compliance. For severe or refractory hypertension, 3 or 4 drugs may be necessary.

Achieving adequate control often requires several evaluations and changes in drug therapy. Reluctance to titrate or add drugs until BP is at an acceptable level must be overcome. Lack of patient adherence, particularly because lifelong treatment is required, can interfere with adequate BP control. Education, with empathy and support, is essential for success.

Antihypertensives for High-Risk Patients

Coexisting Condition

Drug Classes

Cardiovascular risk factors

Beta-blockers

ACE inhibitors

Diuretics

Calcium channel blockers

Chronic kidney disorders

ACE inhibitors

Angiotensin II receptor blockers

Diabetes

Diuretics

ACE inhibitors

Angiotensin II receptor blockers

Calcium channel blockers

Heart failure

ACE inhibitors

Angiotensin II receptor blockers

Beta-blockers

Potassium-sparing diuretics

Other diuretics*

Post-myocardial infarction

ACE inhibitors

Beta-blockers

Spironolactone or eplerenone

Risk of recurrent stroke

ACE inhibitors

Angiotensin II receptor blockers

Calcium channel blockers

Diuretics

*Long-term diuretic use may increase mortality in patients with heart failure who do not have pulmonary congestion.

Devices and physical interventions

Percutaneous catheter-based radiofrequency ablation of the sympathetic nerves in the renal artery is approved in Europe and Australia for resistant hypertension. Hypertension is defined as resistant when BP remains > 160/100 mm Hg despite use of 3 different antihypertensive drugs with complementary mechanisms of action (one of which being a diuretic). Although initial studies appeared promising, a recent large, double-blind study was done (1). This study for the first time incorporated a sham ablation procedure in the control arm and failed to show a benefit from radiofrequency ablation. Thus, sympathetic ablation should still be considered experimental and done only in European or Australian centers with extensive experience.

A second physical intervention involves stimulating the carotid baroreceptor with a device surgically implanted around the carotid body. A battery attached to the device, much like a pacemaker, is used to stimulate the baroreceptor and, in a dose-dependent manner, lower BP. This procedure has so far proven safe and effective, although experience is limited and trials are ongoing. This device is not yet approved in the US for treatment of hypertension.

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